Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data

Abstract

Objective: To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice.

Design: Cohort study emulating a comparative effectiveness trial (target trial).

Setting: Linked primary care, hospital, and death data in England, 2015-21.

Participants: 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin.

Main outcome measures: Primary outcome was absolute change in glycated haemoglobin A_1c (HbA_1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA_1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures.

Results: 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA_1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA_1c change between baseline and one year were -2.5 mmol/mol (95% confidence interval (CI) -3.7 to -1.3) for SGLT-2 inhibitors versus sulfonylureas and -3.2 mmol/mol (-4.6 to -1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking-the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43).

Conclusions: This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA_1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (v DPP-4 inhibitors) and kidney disease progression (v sulfonylureas), with no evidence of differences in other clinical endpoints.

Fig 1

Stacked bar chart illustrating variation in second line antidiabetic treatment prescribed among people included in the study at the clinical commissioning group level in England, 2014-20. DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose cotransporter-2

Fig 2

Flow of study population. *Other antidiabetic drugs prescribed as second line treatment included thiazolidinediones, glucagon-like peptide 1 receptor agonists, and insulin. DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose cotransporter-2

Fig 3

Mean HbA_1c (mmol/mol), estimated glomerular filtration rate (mL/min/1.73m²), body mass index, and systolic blood pressure (mm Hg) at each follow-up time point of interest, stratified by treatment group. DPP-4=dipeptidyl peptidase-4; eGFR=estimated glomerular filtration rate; HbA_1c=glycated haemoglobin A_1c; SBP=systolic blood pressure; SGLT-2=sodium-glucose cotransporter-2

Fig 4

Forest plot showing differences in the mean change between baseline and one year or two years follow-up in continuous clinical measures comparing second line antidiabetic treatments from the instrumental variable analysis to reduce the risk of confounding, and with multiple imputation to account for missing data, which assumes data are missing at random. . CI=confidence interval; DPP-4=dipeptidyl peptidase-4; eGFR=estimated glomerular filtration rate; HbA_1c=glycated haemoglobin A_1c; SGLT-2=sodium-glucose cotransporter 2

Fig 5

Forest plot showing adjusted hazard ratios of cardiovascular disease and kidney outcomes comparing second line antidiabetic treatments from the instrumental variable analysis to reduce the risk of confounding, and with multiple imputation to account for missing data, which assumes data are missing at random. . CI=confidence interval; MACE=major adverse cardiovascular event (composite for the earliest of myocardial infarction, stroke, or cardiovascular death); eGFR=estimated glomerular filtration rate; DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose cotransporter 2